Sleep-Wake Controls Identified, Involved in Coma And Anesthesia Too

How do we wake up? How do we shift from restful sleep to dreaming? Researchers at the University of Arkansas for Medical Sciences (UAMS) have discovered a new brain mechanism that just might explain how we do that. This new mechanism also may help us understand how certain anesthetics put us to sleep and how certain stimulants wake us up

Edgar Garcia-Rill, Ph.D., a professor of neurobiology and developmental sciences in the UAMS College of Medicine and director of the Center for Translational Neuroscience

In their first published study on this topic, researchers in the UAMS Center for Translational Neuroscience found that some neurons in the reticular activating system, a region of the brain that controls sleep-wake states, are electrically coupled.

“By finding drugs for increasing the electrical coupling of these cells, we create a stronger pathway for potential sleep-wake control,” said study author Edgar Garcia-Rill, Ph.D., a professor of neurobiology and developmental sciences in the UAMS College of Medicine and director of the Center for Translational Neuroscience.

“The possible clinical applications range from the ability to wake people up from anesthesia more rapidly, to stimulating someone in a comatose state to awaken if there are enough of these cells left alive to couple them,” Garcia-Rill said.

The study, “Evidence for Electrical Coupling in the SubCoeruleus (SubC) Nucleus,” documenting this cellular new mechanism, was published in the April issue of the Journal of Neurophysiology. In June, the research team presented additional findings at the annual meeting of the Associated for Professional Sleep Societies in Minneapolis.

The researchers found that neurons in the SubCoeruleus nucleus, a part of the brain believed to control the phase of deep sleep known as rapid-eye-movement (REM) sleep, joined in a way that allowed them to transmit electrical activity across the cells. The activity occurred spontaneously or could be induced by chemical agents that induce REM sleep.

The research article was accompanied by an editorial that called the finding “seminal” in the field of sleep-wake research. The editorial was written by peers Matthew Ennis of the Department of Anatomy and Neurobiology at the University of Tennessee Health Center in Memphis and Subimal Datta of the Department of Psychiatry and Behavioral Neuroscience at the Boston University School of Medicine.

“The findings of [the researchers] provide novel and exciting avenues for understanding sleep-wake control as well as for the treatment of sleep and arousal disorders,” wrote Ennis and Datta in the editorial.

Lead author of the study was David S. Heister, a graduate student pursuing a combined medical and doctoral degree in the Department of Neurobiology and Developmental Sciences of the UAMS Graduate School and UAMS College of Medicine.

Joining Heister and Garcia-Rill are Abdallah Hayar, Ph.D., and Amanda Charlesworth, Ph.D., UAMS faculty members in the Department of Neurobiology and Developmental Sciences and researchers in the Center for Translational Neuroscience; Charlotte Yates, Ph.D., from the Department of Physical Therapy at the University of Central Arkansas; and former UAMS faculty member Yi-Hong Zhou, Ph.D., of the University of California-Irvine.

The researchers pointed to earlier work with animal models showing that stimulation of a specific region of the brain, the reticular activating system, produced electrical activity similar to that seen during waking and REM sleep. In studying the SubCoeruleus region of the brain, the researchers detected the presence of electrical coupling of cells, a mechanism that may help the brain switch between the sleep and waking states. The presence of electrical coupling between these cells offers a potential pathway for substances that could better regulate the sleep-wake control, Garcia-Rill said.

The electroencephalogram, or EEG, of the waking brain shows fast rhythms of 10-60 cycles per second, while the sleeping brain cycles at frequencies below 10 per second. Electrical coupling would allow many cells to fire together, generating a rhythm that is transmitted to other parts of the brain to induce changes in sleep-wake states. In collaboration with the chemical transmitters that control the firing rates in individual cells, the two mechanisms could generate any of the frequencies seen in the EEG. Some anesthetics are known to block gap junctions, the channels by which electrical coupling takes place, while some stimulants increase electrical coupling.

SubCoeruleus (SubC) neurons, which are thought to modulate rapid-eye-movement (REM) sleep, were recorded in brain stem slices from 7- to 20-day rats and found to manifest spikelets, indicative of electrical coupling. Spikelets occurred spontaneously or could be induced by superfusion of the cholinergic agonist carbachol. Whole cell recordings revealed that carbachol induced membrane oscillations and spikelets in the theta frequency range in SubC neurons in the presence of fast synaptic blockers. Electrical coupling in neurons is mediated by the gap junction protein connexin 36 (Cx 36). We found that Cx 36 gene expression and protein in the mesopontine tegmentum decreased during development. Cx 36 protein levels specifically in the SubC decreased in concert with the developmental decrease in REM sleep. The presence of electrical coupling in the SubC introduces a novel potential mechanism of action for the regulation of sleep-wake states.